The study was approved by the Hospital Institutional Review Board and registered with the Clinical Trial Registry of China (ChiCTR-1800017696). This manuscript adheres to the applicable 2010 CONsolidated Standards of Reporting Trials (CONSORT) guidelines. Patients who were diagnosed with MG of grade I~II of Osserman classification and scheduled to undergo right sided VATS thymectomy were enrolled in this study between May 2016 and May 2018 after written informed consent. The diagnosis was confirmed by the presence of circulating antibody to the acetylcholine receptor, typical clinical and laboratory findings including ptosis, diplopia, limb weakness, and a decremental conduction response on electrical stimulation of the nerve supply to the deltoid muscle. Exclusion criteria were suspected difficult intubation, body mass index >30 kg.m-2, age less than 18 or over 60 years, hepatic or renal dysfunction, cardiovascular dysfunction, neurologic disorder, operating time greater than four hours, intraoperative blood loss over 1000 ml, history of chronic pulmonary disease, chronic medication with calcium channel blocker or magnesium, and coexisting autoimmune diseases including hyperthyroidism, rheumatoid arthritis, scleroderma or lupus.
The selected patients were randomly assigned to receive magnesium sulfate or normal saline (control). A random sequence was kept within a sealed opaque envelope by a research assistant not involved in this study. On the morning of the surgery, the assistant opened a sealed envelope and prepared the study drug which includes magnesium sulfate (60mg.kg-1 in 50ml normal saline) or 50ml normal saline according to the group allocation. The attending anaesthetists were blinded to the patient’s allocation.
Patients would take their usual dose of anticholinesterase medication and/or steroid on the day of surgery. No premedication was given to the patients. Anaesthesia monitor placed before induction of anaesthesia included pulse oximetry (SpO2), electrocardiograohy (ECG), noninvasive blood pressure (NIBP), arterial blood pressure and bispectral index (BIS™ sensor; Medtronic, Minneapolis, MN, USA). Bispectral index was recorded using BISx Power LinkTM by Philips Medical Systems (Royal Philips Electronics, Eindhoven, The Netherlands). The invasive arterial blood pressure monitor was achieved by left radial artery cannulation under local anaesthesia. An 18G peripheral venous access was placed after performing perioperative checklist was performed with the surgical and nursing team. Patients’ vital signs were recorded and retrieved from the automatic anaesthesia information system.
Anaesthesia was induced with 4µg.kg-1 fentanyl and propofol with target controlled infusion (TCI) using Marsh model (Fresenius Kabi AG, Germany). Propofol TCI was commenced at an effect-site concentration (Ce) of 2µg.ml-1 and titrated to achieve unconsciousness with BIS at 40-60. The patient was ventilated with face mask to maintain the end tidal carbon dioxide between 30-45 mmHg. After the depth of anaesthesia was stable with BIS kept between 40-60 for 10 minutes and a stable Ce of propofol, the electrical stimulation of neuromuscular monitor was applied at the ulnar nerve for the contraction of the adductor pollicis muscle using TOF at amplitude 50mA with time interval at 20 seconds (ISx Power LinkTM by Philips Medical Systems). After the baseline TOF ratio was obtained, the study drug (magnesium sulfate or normal saline) was given over 5 minutes. Another TOF ratio was obtained after study drug infusion was completed. If the TOF ratio was above 10%, a repeated dose of 0.05mg.kg-1 rocuronium was given every 3 minutes until the TOF ratio was less than 10%. The patient was intubated with DLT using video laryngoscopy when TOF ratio was less than 10%. The intubation was performed by an experienced anaesthetist. If the tracheal intubation was not accomplished within 20 s, it was recorded as a failed attempt. Mean blood pressure (MAP) and heart rate (HR) were recorded one minute before intubation (Pre-intubation), and three minutes after intubation (Post-intubation).
Anaesthesia was maintained with propofol using TCI to keep BIS at 40-60. Analgesia was achieved with local anaesthesia infiltration using 0.5% ropivacaine 10ml before skin incision. Remifentanil TCI infusion at 2~4ng.ml-1 was used intraoperatively. No further dose of NMB was administered after induction. Intravenous 40mg parecoxib was administered at 15-30 minutes before the end of operation for postoperative pain, and 4mg ondansetron plus 5 mg dexamethasone was also used for prevention of postoperative nausea and vomiting (PONV). When the surgery was completed, neostigmine 0.05mg.kg-1(along with atropine) and calcium chloride 1g were given to the patient if the TOF ratio was less than 90% or the anaesthetist was not satisfied with the recovery of the respiratory function. During the operation, 5ml.kg-1.h-1 Ringer's lactate solution was given and no Foley catheter was used. Phenylephrine was used to maintain blood pressure when necessary. All thymectomy were conducted with right sided VATS with three ports. Before closing the final incision for VATS, negative suction of chest cavity combined with lung recruitment manoeuvers was employed to re-expand the right collapsed lung, and no postoperative chest drain was used.
The primary outcome of this study was the cumulative rocuronium dose needed to achieve a TOF ratio less than 10% before tracheal intubation. The secondary outcome was intubation condition for DLT placement. The DLT intubation condition quality was evaluated based on Copenhagen Consensus Conference scoring system which includes the ease of laryngoscopy, vocal cord position and/or movement and response to intubation (cough or diaphragmatic movement). Intubation condition was classified as excellent, fair or difficult [16,17]. Other secondary outcomes included were laryngoscopy and intubation induced MAP and HR changes (Post-intubation vs. Pre-intubation), propofol concentration during tracheal intubation, time from the last dose of rocuronium before intubation to TOF ratio 90% recovery, the time to extubation after completion of surgery. Postoperative data collection included the visual analogue score (VAS) for pain, postoperative Riker sedation and agitation scales and PONV status. We classified the patients’ postoperative pain intensity as no pain, mild pain, moderate pain and severe pain with VAS of 0–4 mm, 5–44 mm, 45–74 mm, and 75–100 mm respectively [18]. Utilizing the Riker sedation and agitation scales, we further divided the patients into three categories according to the scale: over sedated (scales 1 - 2), non-agitated (scales 3 - 4) and agitated (scales 5 - 7) [19,20].
Statistical analysis
The sample size estimation was based on the primary outcome (cumulative rocuronium dose used for intubation) in our pilot study. The mean difference of the initial rocuronium dose between the magnesium sulfate group and the normal saline group was 0.14mg.kg-1 with a pooled variance (SD) of 0.11. To obtain an alpha value of 0.05 and a test power of 80%, about 12 subjects were needed in each group. Anticipating about 20% dropout rate, more than 15 subjects were needed in each group. Finally, we planned to recruit 30 patients per group.
Continuous variables presented as mean (SD) or number (%) and were compared by Student t-test. Categorical variables are presented as the number of patients and were compared by Chi-square test or Fisher’s exact test. A P value <0.05 was considered significant. Data analysis was accomplished using MedCalc for Windows, version 11.4.2.0 (MedCalc Software, Mariakerke, Belgium).